Clinicopathological characteristics of hepatocellular carcinoma bearing Mallory bodies: an autopsy study.

Mallory bodies are known to occur in hepatocellular carcinoma. The simple question whether or not there are any clinicopathological features characterizing Mallory body-positive hepatocellular carcinoma remains unresolved to date. The present study of 200 consecutive autopsy cases of hepatocellular carcinoma showed several important differences between 49 cases bearing Mallory bodies and 151 cases bearing no Mallory bodies in carcinoma cells. The patients in the former group were older, showed a higher association rate of liver cirrhosis, and their liver weight was lighter. As to the gross pathology of hepatocellular carcinoma, the nodular type was relatively frequent in Mallory body-positive hepatocellular carcinoma, while the massive and diffuse types were relatively frequent in Mallory body-negative cases. The frequency of extrahepatic metastases in the Mallory body-positive group was lower than that in the Mallory body-negative cases. The reasons for these differences remain speculative.     

Argyrophilic nucleolar organizer regions in neoplastic and non-neoplastic hepatocytes bearing Mallory bodies

ABSTRACT— The proliferative activity of Mallory bodies (MB)-positive hepatocytes (neoplastic and non-neoplastic) was examined by counting the argyrophilic nucleolar organizer regions (AgNORs). Among 19 cases of hepatocellular carcinoma, the mean number of AgNORs was lower in the MB-positive carcinoma cells than in the negative ones in nine cases, higher in six, and there was no difference in four. In non-neoplastic cases (seven cases of advanced primary biliary cirrhosis and seven cases of alcoholic or nutritional liver injury), the mean number of AgNORs was lower in the MB-positive hepatocytes than that in the negative ones in eight cases, and approximately equal in number in six cases. These findings imply that MB formation does not directly represent the level of proliferative activity of hepatocytes, regardless of whether they are malignant or not.     

Mallory bodies and liver diseases

Abstract   Mallory bodies are cytoplasmic inclusions in hepatocytes consisting of abnormal keratins, ubiquitin and several proteins (p62, heat shock proteins) involved in the unfolded protein response. They are morphologic hallmarks of alcoholic and nonalcoholic steatohepatitis but may also be associated with metabolic and toxic liver cell injury and hepatocellular neoplasms. Mallory bodies can be experimentally produced in mouse liver by chronic intoxication with griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mallory body formation is associated with derangement of the keratin intermediate filament cytoskeleton of the hepatocyte. The analysis of Mallory body composition and particularly their experimental induction in animal models and in tissue culture cells disclosed a major role of oxidative stress in the underlying liver cell injury.     

Clinicopathological study of scirrhous hepatocellular carcinoma

BACKGROUND AND AIMS: Scirrhous hepatocellular carcinoma (SHCC) is characterized by diffuse fibrosis of the tumor, however, its clinicopathological features are not fully clarified. This study aimed to clarify the clinicopathological features of SHCC. METHODS: Among 546 consecutively resected HCC without preoperative anticancer therapies, 25 SHCC were selected for the study and compared with 521 cases without scirrhous as the control. RESULTS: SHCC accounted for 4.6% of cases. On diagnostic imagings, SHCC was frequently misdiagnosed as cholangiocarcinoma (CC), combined HCC-CC or metastatic carcinoma. Overall survival rate was significantly higher than the control. The average (+/-SD) tumor size of SHCC was 3.4 +/- 1.8 cm without significant difference to the control. The majority of SHCC (88%) were located close to the liver capsule. SHCC was characterized by stellate fibrosis (84%), no encapsulation (100%), no necrosis and hemorrhage (100%), intratumoral portal tracts (80%), remarkable lymphocyte infiltration (84%), clear cell change (84%), and hyaline bodies (52%). The number of alpha-smooth muscle actin-positive myofibroblast-like cells (activated stellate cells) in the tumor was about three times more than that in the control. Regarding the developmental mechanism of scirrhous change, a close correlation with unique tumor location and activation of stellate cells was suggested. CONCLUSIONS: SHCC presents with characteristic clinicopathological features and the recognition of SHCC is important for both clinicians and pathologists.     

Clinicopathological study of minimum-sized hepatocellular carcinoma: An approach to the definition of early hepatocellular carcinoma

Clinicopathologic examination of 33 nodules from 23 cases of minimum-sized hepatocellular carcinoma (HCC), less than 15 mm in diameter, was carried out by imaging and clinical follow up. On ultrasound (US), 16 hypoechoic nodules (48%) and 15 hyperechoic nodules (45%) on angiography 7 tumour stains (21%) and on computerized tomography (CT) 3 low density nodules (9%) were detected. Of 27 nodules on lipiodol CT (LpCT), 7 lipiodol-deposited nodules (26%) were detected. Of 16 nodules on CO₂US angiography (US-angiography), 7 hypervascular (44%), 5 hypovascular (31%) and 4 isovascular nodules (25%) were detected. Of 13 nodules on CT during arterial portography (CTAP), 7 perfusion defect nodules (54%) were detected. The nodules were graded according to the Edmondson & Steiner Classification. Three nodules were resected; grossly, two were not distinct and one was poorly demarcated. Histologically, they were highly differentiated with irregularly-thin trabecular-patterned HCC where portal triads were detected. Cancer cells invaded the non-cancerous liver cells by replacement, and the border between the cancerous and non-cancerous regions was unclear; the latter region manifested chronic hepatitis or liver cirrhosis without hyperplasia. Minimum-sized HCC is characteristically hypovascular in arterial and portal supply of blood, of multicentric origin and of a well-differentiated pattern. Because the three resected nodules did not damage the liver acinus structure, they were considered to be an early stage of HCC.     

Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer, and clinicopathological features of cHCC-CC have seldom been reported in detail. This study was undertaken to explore the diagnosis and clinicopathological characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), respectively. METHODS: The clinical data from 15 patients with cHCC-CC, 132 patients with HCC and 44 patients with CC who had undergone hepatic resection were analyzed retrospectively. Clinicopathological characteristics of cHCC-CC, HCC and CC such as hepatitis B viral infection, serum hepatitis C virus (HCV) antibody, serum alpha-fetoprotein (AFP) level, cirrhosis, vascular invasion, lymph node metastasis, surgical procedure and adjuvant treatment were also analyzed. Follow up was carried out in the patients, and their 1-, 3-, and 5-year survival rates were calculated. RESULTS: Two patients with cHCC-CC were correctly diagnosed by enhanced CT before operation, the other 13 patients were diagnosed by histology and immunohistochemistry after operation. Radical (8/15) and conservative hepatectomy (7/15) for cHCC-CC was similar to that for HCC and CC (P>0.05). Pathologically cHCC-CC showed more significantly vascular invasion and lymph node metastasis than HCC (P<0.05), and a similarity to CC (P>0.05). Hepatitis B viral infection, serum HCV antibody, cirrhosis, and serum AFP level of cHCC-CC patients were similar to those of HCC patients(P>0.05) but different from CC patients (P<0.05). The cumulative 1-, 3-, and 5-year survival rates in patients with cHCC-CC were poorer than in patients with HCC or CC (P<0.05). CONCLUSIONS: Patients with cHCC-CC are seldom diagnosed before operation. The progression of cHCC-CC is more rapid than that of HCC or CC. Survival rate of patients with cHCC-CC after hepatic resection is poorer than that of patients with HCC or CC.     

Changes of cytokeratin filament organization in human and murine Mallory body-containing livers as revealed by a panel of monoclonal antibodies

ABSTRACT— Mallory bodies (MBs) are characteristic morphologic features of alcoholic hepatitis and can be produced in mouse hepatocytes by chronic griseofulvin (GF) intoxication. The formation of MBs, which share some immunological, biochemical, and ultrastructural features with cytokeratin (CK) filaments of normal liver, is accompanied by derangement and even loss of the CK cytoskeleton of hepatocytes (“empty cells”) as revealed by immunofluorescence microscopy. To clarify whether this diminution or lack of CK-related staining of MB-containing hepatocytes was due to loss of CK filaments or changes in antigenicity or accessibility of antigenic determinants immunohistochemical studies using a battery of monoclonal and polyclonal CK antibodies were performed. It could be shown that all these antibodies directed against different CK polypeptide components and antigenic determinants of CKs revealed a highly reduced or even undetectable cytoplasmic CK meshwork in most cells with fully developed large MBs. In the light of our present knowledge of the organization of CK intermediate filaments, these results indicate that the phenomenon of the “empty cells” reflects a diminution of CK meshwork rather than altered antigenic determinants.     

Juvenile hepatocellular carcinoma with congestive liver cirrhosis

A case of juvenile hepatocellular carcinoma (HCC) with congestive liver cirrhosis is reported. The patient was a 21-year-old woman. She had been diagnosed as having transposition of the great arteries, type 2, in 1978. She underwent the Mustard operation, but suffered from chronic heart failure. In 1995, she experienced abdominal pain and underwent examination. The laboratory data were normal, except for elevated total bilirubin (5.2mg/dl). Blood examinations were performed at frequent intervals, and the total bilirubin level fluctuated between 0.9 and 8.1mg/dl over the next 4 years, but the transaminase level remained normal. In 1999, she experienced abdominal pain again and was admitted to our hospital. Computed tomography showed four space-occupying lesions in the liver; 45mm, 20mm, 12mm, and 10mm in size. She was diagnosed as having HCC, and transcatheter arterial chemoembolization and percutaneous ethanol injection therapy were performed. Histology of the cancerous and the noncancerous liver tissue revealed HCC, moderately differentiated type, in cirrhotic liver with congestion. This patient had no background factors of liver disease, except for liver congestion, associated with the chronic heart failure. Because most patients with cardiac cirrhosis die of cardiac disease, only a small number of these patients develop liver failure. However, the incidence of HCC in patients with congestive liver disease is likely to increase in the future, as survival time is prolonged with the advances in treatment for chronic heart failure. Therefore, patients with congestive liver disease should be followed, taking into account the possibility of HCC.     

Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case-control study of 213 hepatocellular carcinoma patients from India

AIM: To assess the role of hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol intake as risk factors for hepatocellular carcinoma (HCC) in the presence or absence of cirrhosis in Indian population. METHODS: A total of 213 patients with HCC and 254 control subjects not affected with hepatic diseases or neoplasm were recruited. Odds ratios (ORs) were estimated for each risk factor and synergism among various risk factors was also studied. RESULTS: The ORs and 95% confidence intervals (CI) of HCC were 48.02 (25.06-91.98) for any HBV marker, 38.98 (19.55-77.71) for HBsAg positivity, 12.34 (2.84-53.61) for HBsAg negative and antibody positive (either of anti-HBe or total anti-HBc), 5.45 (2.02-14.71) for anti-HCV positive and HCV RNA positive, and 2.83 (1.51-5.28) for heavy alcohol use. No significant risk increase was evident for subjects who were anti-HCV positive and HCV RNA negative. Synergism between alcohol and HCV infection in causing HCC was found, but not between alcohol and HBV. Overall, conclusive evidence of the presence or absence of cirrhosis was reached in 189 (88.73%) HCC patients; cirrhosis was present in 137 (72.48%) of them. ORs with 95% CI of HCC in the presence and absence of cirrhosis, respectively, for HBV were as follows: (i) 48.90 (24.61-97.19) and 35.03 (15.59-78.66) for any HBV marker; (ii) 39.88 (19.41-81.97) and 24.40 (10.60-56.18) for HBsAg positivity; and (iii) 12.10 (2.67-54.88) and 19.60 (3.94-97.39) for HBsAg negativity and antibody positivity. Significantly increased risk was found among cirrhotic patients for anti-HCV positivity and HCV RNA positivity [OR = 7.53 (2.73-20.78)] and for heavy alcohol use [OR = 3.32 (1.70-6.47)]; however, in the absence of cirrhosis, no significant risk increase was evident for subjects who were anti-HCV positive and HCV RNA positive [OR = 0.97 (0.11-8.54)], or who had history of heavy alcohol use [OR = 1.58 (0.55-4.53)]. CONCLUSIONS: Infection with HBV and HCV are the major risk factors for the development of HCC in Indian patients. Presence of HBV antibodies even in the absence of HBsAg conferred increased risk for HCC in the presence or absence of cirrhosis. Anti-HCV positivity in the absence of HCV RNA conferred no increased risk. HCV RNA positivity and heavy alcohol use significantly increased the risk of HCC among cirrhotic patients, but not non-cirrhotic patients.     

Prolonged bleeding time: A new clinical manifestation of hepatocellular carcinoma?

The association between prolonged bleeding time and hepatocellular carcinoma (HCC) has not been well studied. We investigated whether bleeding time is prolonged in cirrhotic patients with HCC and studied the role of clinical characteristics, tumour size, and laboratory data in predicting bleeding time prolongation. After excluding patients that presented with blood dyscrasia and uraemia, 58 cirrhotic patients with HCC, 106 cirrhotic patients without HCC, and 44 age- and sex-matched healthy subjects were included in the study. Bleeding time, imaging studies, clinical characteristics and biochemical data were obtained for every patient. Cirrhotic patients with and without HCC had longer bleeding times (554±68 and 535±32s, respectively) compared with healthy controls (357±13s, P < 0.05). Hepatocellular carcinoma patients with a large tumour burden (> 5 cm in diameter) had a significantly longer bleeding time than those patients without (663±105 vs 376±23s, respectively, P < 0.05). After excluding patients with a platelet count ≤ 80 000/mm³, cirrhotic patients classified as Child-Pugh's grading A and with a large tumour burden had longer bleeding times (580±87s) than patients with a small tumour burden (≤ 5 cm in diameter) and cirrhotic patients without HCC (371±22 and 416±29s, respectively, P < 0.05). In cirrhotic patients with HCC, higher serum bilirubin levels, a Child-Pugh's grading C, and a tumour size > 5 cm in diameter were found to be significant predictors for prolonged bleeding time on univariate analysis. On multivariate analysis, both tumour size > 5 cm in diameter and a Child-Pugh's grading C (odd's ratio, 95% confidence interval and P value were measured as 38.5, 2.8–534.7, < 0.001, and 10.5, 0.9–117.6, 0.02, respectively) were the significant independent predictors. A significant correlation existed between tumour diameter and bleeding time (r= 0.44, P < 0.01). In conclusion, these results suggest that prolonged bleeding time may be categorized as a new clinical manifestation in patients with HCC. In addition to cirrhosis, HCC itself may also participate in the pathogenesis of bleeding time prolongation.     

Nonalcoholic steatohepatitis: cirrhosis,hepatocellular carcinoma,and burnt-out NASH

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by the histological features of steatohepatitis in the absence of significant alcohol consumption. The natural history of NASH is poorly defined. Here we report our experience with a patient to illustrate the clinical course of cirrhotic NASH. A 67-year-old woman was admitted with hematemesis due to the rupture of esophageal varices. Her varices were treated by endoscopic ligation and endoscopic sclerotherapy. Her medical history was unremarkable. Both the patient and her family members were asked about alcohol intake several times during her illness, but all of them denied a history of alcohol intake. She had insulin resistance, as determined by homeostasis model assessment. Serological tests for viral hepatitis were all negative. Viral hepatitis, autoimmune liver disease, iron overload, and metabolic liver disorders were all excluded. Imaging tests failed to reveal any steatosis, because of the presence of severe fibrosis. Liver biopsy showed moderate steatosis, moderate inflammation, ballooning degeneration, and Mallory bodies. We diagnosed NASH associated with cirrhosis based on the clinicopathological features. Almost 2 years later, she developed hepatocellular carcinoma (HCC) and she died of multiple HCCs. At autopsy, tumor invasion was seen throughout liver segment 8. The noncancerous liver showed burnt-out NASH; the steatosis, necroinflammation, ballooning degeneration, and Mallory bodies had all disappeared. In Japan, the prevalence of nonalcoholic fatty liver disease will increase as obesity has been increasing, so it is important to understand how to diagnose NASH. When a patient has NASH, careful follow-up should be performed.     

Survival in hepatocellular carcinoma: impact of screening and etiology of liver disease

BACKGROUND AND AIMS: As the merits of screening at-risk populations for hepatocellular carcinoma (HCC) remain unclear, we compared the clinico-pathologic features and survival of patients with cirrhosis and HCC detected by screening (Group A) to that in non-screened cases (Group B). METHODS: We studied cirrhotics who developed HCC between 1994 and 2002. During this period, cirrhotics managed by the Gastroenterology Unit were regularly screened at 6-12 monthly intervals while those managed by other hospital units were not. Demographic data, tumor details, treatment received and survival were recorded and compared according to screening status. RESULTS: There were 96 cases identified; 41 by screening (group A) and 55 by non-screening methods (Group B). HCC in Group A were smaller (P < 0.01), more likely unilobar (P < 0.01), at an early stage (P < 0.0005) and before vascular invasion (P < 0.005) than Group B cases. The frequency of hepatic surgery and/or local ablation was higher in Group A than Group B (P = 0.001). Overall median survival of Group A was 882 days versus 99 days in Group B (P < 0.0001). One- and 3-year probabilities of survival in Group A were 89% and 38%, versus 33% and 19% in Group B (P < 0.001). Independent predictors of survival included screening, Child-Pugh score, creatinine, tumor stage and absence of alcohol as the etiology. CONCLUSIONS: Screening for HCC in cirrhosis identifies tumors at an earlier stage, results in a higher chance of receiving curative treatment and possibly improves patient survival. The absence of alcoholic liver disease impacts favorably on survival.     

Spontaneous partial regression of hepatocellular carcinoma in a cirrhotic patient

Spontaneous regression of a malignant tumor is an exceptional phenomenon. A 56-year-old woman with liver cirrhosis related to chronic hepatitis C presented with a liver tumor. Partial regression of a hepatocellular carcinoma was diagnosed by imaging studies that showed progressive diminution of the size of the tumor and changes in the tumor markers. However, because of the persistence of the tumor and uncertainty in the diagnosis we recommended surgery. A hepatectomy was performed and a hepatocellular carcinoma moderately differentiated was found. The patient is now doing well and without any evidence of recurrence at 25 months after surgery. We found 61 case reports that have been published from 1982 to September 2006, with apparently spontaneous regression of hepatocellular carcinoma. The precise mechanism regarding the spontaneous regression of this tumor is not fully understood, either ischemia due to rapid growth of the neoplasia or particular inflammatory and immunologic mechanisms may be involved in the regression of the hepatocellular carcinoma.     

Arteriovenous malformation of the pancreas associated with hepatocellular carcinoma

Summary A case of pancreatic arteriovenous malformation (AVM) with hepatocellular carcinoma is reported. The patient, a 56-year-old Japanese man, was asymptomatic. The pancreatic lesion was found incidentally during an evaluation for hepatocellular carcinoma. Celiac arteriogram demonstrated tortuous feeding arteries, a racemose intrapancreatic stain, which disappeared before the venous phase, and early portal filling.     

Laparoscopic hepatectomy for hepatocellular carcinoma in cirrhotic patients

Introduction

We have used laparoscopic hepatectomy as a surgical treatment for HCC in patients with cirrhosis. We describe the indications, evaluate invasiveness and analyze the outcomes of laparoscopic hepatectomy.

Methods and Results

With respect to operative method, laparoscopic hepatectomy involving either partial hepatectomy or left lateral sectionectomy is a less invasive procedure in patients with cirrhosis than conventional hepatectomy. Among our laparoscopic hepatectomy cases, operative time was shorter and bleeding was less in recent, as compared to earlier, cases. Furthermore, laparoscopic hepatectomy was less invasive than conventional hepatectomy, as determined by the E-PASS scoring system. Patients also recovered more quickly, which resulted in shorter hospital stays even for patients with cirrhosis. Both the 5-year survival rate and the rate of survival without recurrence of HCC were nearly identical to those of open conventional hepatectomy.

Conclusion

These findings indicate that laparoscopic hepatectomy avoids the disadvantages of standard hepatectomy for HCC in properly selected patients with cirrhosis and that its minimal invasiveness improves patients’ quality of life.     

Laparoscopic prediction of hepatocellular carcinoma in cirrhosis patients

Previously, laparoscopic studies have not been successful in predicting the occurrence of small hepatocellular carcinoma because cirrhotic patients had not been separated into groups of those who developed small hepatocellular carcinoma under 3 cm in diameter, and those who did not. Retrospective examination with better separation of the two groups gave improved results. Of the 26 laparoscopic findings, only the presence of large complex regenerative nodules was closely associated with the occurrence of subclinical small hepatocellular carcinoma. The study of other cirrhotic patients with and without large complex regenerative nodules gave a cumulative hepatocellular carcinoma occurrence rate of 73% for patients who had these nodules by the third year after laparoscopy. In contrast, the rate for patients without such nodules was 6%, showing a significant difference (P < 0.05) between the two groups. We concluded that the laparoscopic finding of large complex regenerative nodules of liver cirrhosis can be used to predict the occurrence, or a complication, of subclinical small hepatocellular carcinoma.     

Hepatitis C virus and hepatocellular carcinoma

The sequential development of cirrhosis and hepatocellular carcinoma (HCC) in patients with transfusion-associated hepatitis was a clue leading to the identification of hepatitis C virus (HCV) as a risk factor for HCC. The incidence of HCV-related liver cancer is increasing in many developed countries: tumours arise in older patients, are almost invariably associated with cirrhosis and often have a less aggressive course than is seen in HCC related to other aetiological factors. Most HCCs grow as a single hepatic nodule for several years before generating satellite or distant tumour nodules. Tumour progression and hepatic failure are the leading causes of death. HCV might promote cancer through cirrhosis, which is per se an important risk factor for this tumour. HCV might also have oncogenic properties by interacting with cellular genes that regulate cell growth and differentiation. The primary prevention of HCC through vaccination against HCV is not yet available. The treatment of patients with chronic hepatitis C with interferon might attenuate the risk of HCC.